Patient autoantibodies induce platelet destruction signals via raft-associated glycoprotein Ibα and Fc RIIa in immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by thrombocytopenia in the absence of an underlying cause.1 The patho-physiology of ITP is multifactorial and includes the development of autoantibodies that trigger abnormal thrombopoiesis, enhanced platelet destruction, complement activation and T-cell mediated effects.1–3 Platelet autoantibodies are detected in approximately 50% of patients4 and generally target the fibrinogen receptor αIIbβ3 or the receptor for von Willebrand factor (VWF), the glycoprotein (GP) Ib-V-IX complex. Anti-αIIbβ3 antibodies (70–80% of cases) are thought to induce thrombocytopenia through increased platelet clearance by Fcγ receptor-bearing macrophages. Autoantibodies against GPIb-V-IX (20–40% of cases) often induce a more severe fall in platelet count5 that is less responsive to standard therapies, such as intravenous immunoglobulin G (IVIG).6 Thrombocytopenia induced by GPIb-V-IX autoantibodies has not been characterized in great detail. Some monoclonal antibodies against GPIbα are known to induce platelet activation7 that may lead to accelerated platelet destruction in ITP patients8 with autoantibodies against this receptor. Here we report how an autoantibody against GPIbα, obtained from a patient with ITP, induces recognition signals for macrophages through interplay between glycoprotein Ibα and the low affinity IgG receptor FcγRIIa in lipid rafts.